Accession Number : ADA462351


Title :   Smallpox Antiviral Drug


Descriptive Note : Annual rept. 1 Jan-31 Dec 2005


Corporate Author : SIGA TECHNOLOGIES INC CORVALLIS OR


Personal Author(s) : Hruby, Dennis E.


Full Text : http://www.dtic.mil/get-tr-doc/pdf?AD=ADA462351


Report Date : JAN 2006


Pagination or Media Count : 17


Abstract : Using a homology-based bioinformatics approach, a structural model of the vaccinia virus (VV) I7L proteinase was developed at Transtech Pharma. A unique chemical library of ~ 51,000 compounds was computationally queried to identify potential active site inhibitors. The resulting biased subset of compounds was assayed for both toxicity and the ability to inhibit the growth of VV in tissue culture cells and found to target the I7L enzyme. However, after several rounds of medicinal chemistry the chemists were not able to improve the pharmacokinetic and toxicological properties of this series of compounds. SIGA has since designed a new structural model of the I7L active site based on the Ulp1 cysteine proteinase (PDB: 1euv). Commercially available small molecule libraries that total approximately 1 million compounds are currently being queried to identify potential inhibitors. Potential active site inhibitors are being purchased and tested in the recently developed in vitro I7L cleavage assay. A new fluorescence anisotrophy cleavage assay is under development and will be converted to a high-throughput screen if possible. SIGA has a 200,000 small molecule library that could be used for screening in a HTS cleavage assay. The final goal of this project is the identification of a potent antiviral against various pox viruses ready for preclinical development.


Descriptors :   *ANTIVIRAL AGENTS , *VARIOLA VIRUS , TISSUE CULTURE CELLS , ENZYMES , VACCINIA VIRUS , POX VIRUSES , INHIBITORS , DRUGS


Subject Categories : MICROBIOLOGY
      PHARMACOLOGY


Distribution Statement : APPROVED FOR PUBLIC RELEASE